A5009334933- Cancer Immunotherapy and Biomarkers
- Estrogen and related hormone effects
- Cancer Cells and Metastasis
- Immunotherapy and Immune Responses
- BRCA gene mutations in cancer
- RNA Research and Splicing
- MicroRNA in disease regulation
- Cancer Genomics and Diagnostics
- Gene expression and cancer classification
- Breast Cancer Treatment Studies
- Cancer-related molecular mechanisms research
- Genomics and Chromatin Dynamics
- HER2/EGFR in Cancer Research
- PI3K/AKT/mTOR signaling in cancer
- Molecular Biology Techniques and Applications
- Endometrial and Cervical Cancer Treatments
- Cancer Treatment and Pharmacology
- DNA Repair Mechanisms
- Advanced Breast Cancer Therapies
- Genetics, Bioinformatics, and Biomedical Research
- PARP inhibition in cancer therapy
- Bioinformatics and Genomic Networks
- Dutch Social and Cultural Studies
- Comparative and International Law Studies
- Epigenetics and DNA Methylation
The Netherlands Cancer Institute
2015-2024
Oncode Institute
2015-2024
Reinier de Graaf Hospital
2017-2018
University Medical Center Utrecht
2012-2018
Amsterdam UMC Location Vrije Universiteit Amsterdam
2018
Deventer Ziekenhuis
2017
Haga Hospital
2017
Zaans Medisch Centrum
2017
Dutch Cancer Society
2017
Radboud University Medical Center
2017
Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated a favorable prognosis in TNBC. However, whether this association holds for who are node-negative (N0), (< 40 years), chemotherapy-naïve, thus can be used chemotherapy de-escalation strategies, unknown.We selected N0 diagnosed between 1989 2000 from Dutch...
The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative HER2-positive breast cancer. However, the role TILs luminal cancer less clear. Emerging evidence has now demonstrated that genetic aberrations malignant cells influence immune landscape tumors. Phosphatidylinositol 3-kinase (PI3K) most common altered pathway ER-positive It unknown whether changes PI3K result a different composition tumor...
Abstract Breast cancer tumor grade is strongly associated with patient survival. In current clinical practice, pathologists assign after visual analysis of tissue specimens. However, different studies show significant inter-observer variation in breast grading. Computer-based grading methods have been proposed but only work on specifically selected areas and/or require labor-intensive annotations to be applied new datasets. this study, we trained and evaluated a deep learning-based model...
Abstract Introduction Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently are lacking. PIK3CA mutations frequently occur ERα-positive cancer result vitro . Nevertheless, prognostic treatment-predictive value these is contradictive. We tested clinical validity other...
Abstract The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence‐free (RFS) and overall survival (OS) in patients stage III ovarian cancer. Homologous recombination deficient (HRD) tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD respond best treatment HIPEC. We analyzed the effect HIPEC OVHIPEC trial, stratified by status BRCA m status....
The suggestion that the systemic immune response in lymph nodes (LNs) conveys prognostic value for triple-negative breast cancer (TNBC) patients has not previously been investigated large cohorts. We used a deep learning (DL) framework to quantify morphological features haematoxylin and eosin-stained LNs on digitised whole slide images. From 345 patients, 5,228 axillary LNs, cancer-free involved, were assessed. Generalisable multiscale DL frameworks developed capture germinal centres (GCs)...
The level of tumour-infiltrating lymphocytes (TILs) is a prognostic factor for patients with (triple-negative) breast cancer (BC). Computational TIL assessment (CTA) has the potential to assist pathologists in this labour-intensive task, but current CTA models rely heavily on many detailed annotations. We propose and validate fundamentally simpler deep learning based that can be trained only ten minutes hundredfold fewer pathologist collected whole slide images (WSIs) TILs scores clinical...
Abstract Introduction Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance vitro , but a biomarker with clinical validity to predict intrinsic has not been identified. In metastatic breast cancer patients previous exposure endocrine therapy, addition mammalian target rapamycine (mTOR) inhibitor shown be beneficial. Whether or on adjuvant treatment might benefit from these drugs is currently unclear....
In previous studies, high expression of XIST and low 53BP1 were respectively associated with poor systemic therapy outcome in patients resistance BRCA1-deficient mouse tumor models, but have not been evaluated patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified enriched for defects BRCA1 benefit from high-dose (HD) alkylating chemotherapy compared a conventional standard regimen. We investigated whether...
Abstract Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature (“BRCA1-like”) and are hypersensitive to double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human tumors might predict sensitivity DSB-inducing drugs; (ii) inhibition potentiates cisplatin efficacy Brca1-deficient murine mammary tumors. Experimental Design: expression was analyzed 497 using IHC or RNA sequencing. We classified 370 by profiles as...
Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in recurrent disease resistance to tamoxifen therapy is common a major cause death. In recent years, in‐depth proteome analyses have enabled identification clinically useful biomarkers, particularly, when heterogeneity complex tumor tissue was reduced using laser capture microdissection (LCM). current study, we performed high...
Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks endometrial cancer. However, no parallels ERα transcriptional action in and tumors have been found that might explain this effect. In study, we addressed issue with genome-wide assessment ERα-chromatin interactions surgical specimens obtained from patients tamoxifen-associated was at active enhancers cancer cells as marked by presence RNA polymerase II...
Glucocorticoid receptor (GR) is a transcription factor that plays crucial role in cancer biology. In this study, we utilized an silico-designed GR activity signature to demonstrate relates the proliferative capacity of numerous primary types. breast cancer, status determines luminal subtype identity and has implications for patient outcomes. We reveal engages with estrogen (ER), leading redistribution ER on chromatin. Notably, activation leads upregulation ZBTB16 gene, encoding...
•Oncologists treat most eTNBC patients with chemotherapy due to a lack of implemented prognostic and predictive biomarkers.•We studied cohort systemic treatment-naïve young women node-negative 20 years median follow-up.•LVI (HR 2.35), fibrotic focus 1.61) sTILs 0.75 per 10% increment) had independent value for BCSS.•The presence LVI <30% identified an ultra-high risk recurrence or death.•De-escalation trials should consider the exclusion when is present. BackgroundIn absence biomarkers,...
Both preclinical and clinical data suggest that activation of the PI3K/AKT/mTOR pathway in response to hormonal therapy results acquired endocrine resistance. We evaluated differences estrogen receptor α (ERα) positive primary corresponding metastatic breast cancer tissues using immunohistochemistry for downstream activated proteins, like phosphorylated mTOR (p-mTOR), 4E Binding Protein 1 (p-4EBP1) p70S6K (p-p70S6K). For p-mTOR p-4EBP1, proportion immunostained tumor cells (0-100%) was...
Abstract Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance common. In this study, we refined previously identified 111-gene outcome prediction-classifier, revealing FEN1 as strongest determining factor patient prognostication. levels were predictive tamoxifen-treated patients, and played causal role ERα-driven cell growth. impacted activity ERα by facilitating coactivator...
Abstract Background The addition of adjuvant capecitabine to standard chemotherapy early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and meta-analyses. However, many did not benefit. We evaluated the BRCA1 -like DNA copy number signature, indicative homologous recombination deficiency, as predictive biomarker for benefit TNBC subgroup FinXX trial. Methods Early-stage were between capecitabine-containing (TX + CEX:...
Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of signaling on tamoxifen benefit patients and we searched for approaches to overcome IGF-1R-mediated failure cell lines. Primary tumor blocks from postmenopausal ER+ cancer randomized between adjuvant versus nil were recollected. Immunohistochemistry IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) PI3K/MAPK...
// Tommaso De Marchi 1 , Anne M. Timmermans Marcel Smid Maxime P. Look Christoph Stingl 2 Mark Opdam 3 Sabine C. Linn Fred G. J. Sweep 4 Paul N. Span 5 Mike Kliffen 6 Carolien H. van Deurzen 7 Theo Luider John A. Foekens W. Martens 1, 8 Arzu Umar Department of Medical Oncology, Erasmus MC Cancer Institute, University Center, Rotterdam, The Netherlands Neurology, Division Institute – Antoni Leeuwenhoek Hospital, Amsterdam, Laboratory Medicine, Radboud Nijmegen, Radiation Pathology, Maasstad...
We recently reported on the development of a 4-protein-based classifier (PDCD4, CGN, G3BP2, and OCIAD1) capable predicting outcome to tamoxifen treatment in recurrent, estrogen-receptor-positive breast cancer based high-resolution MS data. A precise high-throughput assay measure these proteins multiplexed, targeted fashion would be favorable large numbers patient samples move findings toward clinical setting. By coupling immunoprecipitation multiple reaction monitoring (MRM) stable isotope...
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to inhibitors remain major clinical challenges. Here, we show that MYC activation drives mTOR (mTORi) in cancer. Multiomic profiling mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications acquired mTORi AZD8055. was associated with biological processes linked counteracted mTORi-induced translation...
Estrogen catabolism is a major function of CYP2C19. The effect CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by variation in metabolite levels but also an breast cancer risk and molecular subtype due to lifelong exposure estrogens. We determined the association between these context randomized trial, which allows for discernment prognosis from prediction. isolated primary tumor DNA 535 estrogen receptor-positive, stages I–III, postmenopausal patients who...
The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result antioestrogen resistance. Single markers failed to be introduced into clinical practice. We, therefore, aimed find a better read-out of activation the PI3K and MAPK ER+/HER2− cancer. Assessment seven PI3K/MAPK proteins might reflect pathway distinguish patients without adjuvant tamoxifen benefit. Tumour blocks were recollected from 293...